Resolvin D5 (RvD5) is a specialized pro-resolving lipid mediator with potent anti-inflammatory and analgesic properties. Orofacial pain conditions, especially those that are chronic, present clinical challenges in terms of pharmacological management. Thus, new therapeutic options are clearly warranted. Herein, we investigated the antinociceptive effect of RvD5 in the chronic constriction injury of the infraorbital nerve (CCI-ION) model and in the orofacial formalin test in female and male Wistar rats. Our results indicated that repeated subarachnoid medullary injections of RvD5 at 10 ng resulted in a significant reduction of heat and mechanical hyperalgesia induced by the CCI-ION in male and female rats, but males were more sensitive to RvD5 effects. In addition, after CCI-ION, interleukin-6 (IL-6) level was increased in the trigeminal nucleus caudalis of male, but not female rats, which was reduced by RvD5 repeated treatment. No changes in the levels of IL-1β were found. Minocycline blocked the effect of RvD5 in male rats but failed to affect RvD5 antinociceptive effect in females. Moreover, a single medullary injection of RvD5 caused a significant reduction of formalin-induced facial grooming, in phases I and II of the test, but only in male rats. This study demonstrated for the first time the analgesic effect of RvD5 in trigeminal pain models, and corroborated previous evidence of sex dichotomy, with a greater effect in males. This article presents a translational potential of RvD5 for targeted therapies aiming at the control of acute and chronic trigeminal pain, but further studies are needed to elucidate its sex-related mechanisms. Perspective: This study demonstrated that RvD5 may provide benefits for trigeminal neuropathic pain treatment in male and female rats, but its effect on inflammatory orofacial pain seems to be restricted only to males. Also, it provided evidence for sex dichotomy in the mechanisms related to the antinociceptive effect of RvD5.